The pathway of uridine monophosphate synthesis has been studied extensively and is reasonably well understood. It has been determined that oritidine monophosphate (OMP) decarboxylase catalyzes the conversion of oritidine monophosphate to uridine monophosphate, in the de novo biosynthesis of pyrimidines, an initial step in de novo DNA synthesis. It has also been determined that OMP decarboxylase is inhibited by a range of mononucleotides, the precursors of which include barbiturate (a.k.a. 6-hydroxyuridine), 6-azauridine, uridine, allopurinol and oxipurinol. Levine et al, Biochem. 19:4993-4999 (1980); Potvin et al, Biochem. Pharm. 27:655-665 (1978); Hauser et al, N. Engl. J. Med. 322:1641-1645 (1990). The inhibition of OMP decarboxylase results in the accumulation of orotidine and orotate. The pathway of pyrimidine mononucleotide biosynthesis and the mechanism of action of various OMP decarboxylase inhibitors and precursors thereof is shown in FIG. 1.
Allopurinol induced pyrimidinuria (orotic aciduria and/or orotidinuria) has been shown to be a sensitive and specific test that identifies the increased de novo pyrimidine mononucleotide biosynthesis accompanying ornithine transcarbamylase (OTC) deficiency. The test has been standardized and helps to establish a diagnosis in women at risk for having a mutation at the OTC locus on the X chromosome. Hauser et al, N. Engl. J. Med. 322:1641-1645 (1990), correction N. Engl. J Med. 336:1335 (1997); Burlina et al, J. Inher. Metab. Dis. 15:707-712 (1992); Pineda et al, Medicina Clinica 101:383-386 (1993); Maestri et al, Amer. J. Hum. Genet. 59:A378 (1996). In this prior test, allopurinol is administered to patients, and the levels of orotate and/or orotidine were measured. Orotate and oritidine levels are considered abnormal if they are three standard deviations above the mean value of normal (control) samples.
It is desirable to have a screening process which detects cancer in its early stages. Such a screening process may be an invaluable tool in detecting the cancer in time for early treatment, which translates into a higher survival rate and less traumatic recovery for the patient. A screening process that is non-invasive is highly desirable, to ensure that patients will be willing to undergo the screening process. A screening process is most useful when it can follow the history of a patient who is at risk of developing cancer, due to genetic history or other statistical measure of risk.
The present inventor has discovered that increased de novo pyrimidine biosynthesis (and, hence, de novo DNA biosynthesis), which is a characteristic of malignant solid tumors, may be determined by using OMP decarboxylase inhibitor precursors. This discovery may be incorportated into a screening process for determining the presence or absence of cancer. This discovery can also be used to monitor the effectiveness of cancer treatment.